Objective

HYPOTHESIS: Early inhalation of Budesonide (BS) reduces the absolute risk of developing bronchopulmonary dysplasia (BPD) or death in preterm infants born between 23 and 27 weeks gestational age (GA) by 10%. PRIMARY OBJECTIVE: Survival without BPD at 36 weeks GA. SECONDARY OBJECTIVES: (1) neurodevelopment at a corrected age of 18-22 months; (2) adverse treatment effects; (3) mortality at 36 weeks GA; (4) BPD incidence at 36 weeks GA; (5) duration of positive pressure respiratory support or supplemental oxygen; (6) pharmacokinetic-pharamacodynamic analyses. RATIONALE: Inflammation is central to the development of BPD. Corticosteroids (CS) have antiinflammatory properties and early inhalation of CS may allow for beneficial local effects on the pulmonary system with a lower risk of undesirable systemic side effects. STUDY DESIGN: Randomised placebo-controlled, multi-centre clinical trial and genetic/pharmacogenetic substudy. RESEARCH PLAN: Within 2 years 850 infants of 23-27 weeks GA will be randomised during the first 12 hours of life to BS or placebo to prevent BPD. Study drugs will be administered via Aerochamber and continued until infants are either off supplementary oxygen and positive pressure support or have reached a GA of 32 0/7 weeks regardless of ventilatory status. Study patients will be followed and neurodevelopmental outcomes will be assessed at a corrected age of 18-22 months. CLINICAL SIGNIFICANCE: BPD contributes to the mortality of preterm infants and is associated with impaired neurosensory development and an increased risk of pulmonary morbidity in adolescence and young adulthood. Systemic CS are effective in preventing BPD, but their use is practically prohibited given their adverse effects on neurodevelopment. Early inhalation of CS has been shown to be associated with secondary pulmonary benefits, but its effect on survival without BPD and on neurodevelopment remains unclear.

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Improving lung disorders in premature babies

Bronchopulmonary dysplasia (BPD) is a chronic lung disorder that is most common among children who are born prematurely. A safe therapy for BPD treatment would be extremely valuable from an individual patient as well as an economic health care perspective.

BPD involves abnormal development of lung tissue, and is characterised by inflammation and scarring in the lungs. It develops most often in premature babies, who are born with underdeveloped lungs. BPD results in significant morbidity and mortality.
Systemic corticosteroids are effective in preventing BPD, but their use is practically prohibited given their adverse effects on neurodevelopment. Early inhalation of corticosteroids is associated with pulmonary benefits, but its effect on survival without BPD and on neurodevelopment remains unclear.
The EU funded the NEUROSIS project to determine whether early inhalation of corticosteroid budesonide improves survival without BPD at 36 weeks of gestation in infants born between 23 and 27 weeks. NEUROSIS is an international multi-centre randomised controlled blinded study in a population of 850 pre-term infants.
Approvals from the national competent authorities and the research ethics boards have been obtained in all countries. The project will focus on data analysis and the follow-up of neurodevelopmental assessment.NEUROSIS is one of the largest randomised controlled studies in pre-term neonates ever conducted in Europe. Its results have the potential to make an important impact on the economics of premature baby health care.

Final Report Summary - NEUROSIS (Efficacy and Safety of Inhaled Budesonide in Very Preterm Infants at Risk for Bronchopulmonary Dysplasia)

Executive Summary:Background and rationaleBronchopulmonary dysplasia (BPD) contributes to the mortality of preterm infants and is as-sociated with impaired neurosensory development and an increased risk of pulmonary mor-bidity in adolescence and young adulthood. Early systemic corticosteroids reduce the risk of BPD in extremely preterm infants, but they may negatively affect the developing brain. The effects of inhaled corticosteroids on outcomes in these infants are unclear.

Plan at outsetThe Neonatal European Study of Inhaled Steroids (NEUROSIS) is a randomized placebo-controlled, international clinical trial. We planned to randomize 850 infants of 23-27 weeks' postmenstrual age during the first 12 h of life to budesonide or placebo. We intended to de-termine the primary outcome of survival without BPD at 36 weeks' postmenstrual age and to follow our study patients and assess neurodevelopmental outcomes at a corrected age of 18-22 months.

Objectives achievedBetween 2010 and 2013, we randomized 863 infants (gestational age of 23 0/7 to 27 6/7 weeks) to early inhaled budesonide or placebo in 40 study centres in 8 European countries and in Israel. The primary outcome was death at 36 weeks or bronchopulmonary dysplasia. Of 437 infants assigned to budesonide, 175 died or had bronchopulmonary dysplasia (40.0%), compared with 194 of 419 assigned to placebo (46.3%) (relative risk, stratified for gestational age, 0.86; 95% CI 0.75-1.00; P=0.05). The rate of bronchopulmonary dysplasia was 27.8% in the budesonide group vs. 38.0% in the placebo group (relative risk, stratified for gestational age, 0.74; 95% CI, 0.60-0.91; P=0.004) and mortality was 16.9% vs. 13.6% respectively (relative risk, stratified for gestational age, 1.24; 95% CI 0.91-1.69; p=0.17). An assessment of neurodevelopmental disability is currently being conducted at 18-22 months corrected age and the results will be available in 2016.

ConclusionThe primary objectives of NEUROSIS were achieved completely. The assessment of the long-term follow-up is ongoing until 2016 and the results will be very important for future guidance.